MECHANISM OF MITOTIC BLOCK AND INHIBITION OF CELL-PROLIFERATION BY TAXOL AT LOW CONCENTRATIONS
MECHANISM OF MITOTIC BLOCK AND INHIBITION OF CELL-PROLIFERATION BY TAXOL AT LOW CONCENTRATIONS
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DOI：
10.1073/pnas.90.20.9552
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发表时间：
1993-10-15
影响因子：
11.1
通讯作者：
WILSON, L
中科院分区：
文献类型：
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作者：
JORDAN, MA;TOSO, RJ;WILSON, L
紫杉醇通过在中期/后期边界诱导持续的有丝分裂阻滞来抑制HeLa细胞增殖。细胞增殖的半数最大抑制发生在8 nM紫杉醇时，有丝分裂在8 nM紫杉醇时被半数最大阻断。有丝分裂的抑制与染色体不完整中期板的形成和纺锤体微管排列的改变有关，这种改变与低浓度长春碱和其他抗有丝分裂化合物发生的异常组织非常相似。在低于10 nM紫杉醇时，微管聚合物质量没有增加。微管的质量在80 nM紫杉醇时增加了一半，在330 nM紫杉醇时达到最大水平（正常值的5倍）。在亚微摩尔浓度下，紫杉醇抑制生长和缩短的微管在体外重组牛脑微管蛋白的方式类似于长春碱抑制。紫杉醇在HeLa细胞中被浓缩了几百倍，达到了与体外抑制动态不稳定性的水平相似的水平。结果表明，紫杉醇与长春碱具有共同的抗增殖机制。在其最低有效浓度下，紫杉醇似乎通过动力学稳定纺锤体微管而不是通过改变聚合微管的质量来阻断有丝分裂。
Taxol inhibited HeLa cell proliferation by inducing a sustained mitotic block at the metaphase/anaphase boundary. Half-maximal inhibition of cell proliferation occurred at 8 nM taxol, and mitosis was half-maximally blocked at 8 nM taxol. Inhibition of mitosis was associated with formation of an incomplete metaphase plate of chromosomes and an altered arrangement of spindle microtubules that strongly resembled the abnormal organization that occurs with low concentrations of vinblastine and other antimitotic compounds. No increase in microtubule polymer mass occurred below 10 nM taxol. The mass of microtubules increased half-maximally at 80 nM taxol and attained maximal levels (5 times normal) at 330 nM taxol. At submicromolar concentrations, taxol suppressed growing and shortening at the ends of microtubules reassembled in vitro from bovine brain tubulin in a manner that resembled suppression by vinblastine. Taxol was concentrated in HeLa cells several hundredfold to levels that were similar to those which suppressed dynamic instability in vitro. The results indicate that taxol shares a common antiproliferative mechanism with vinblastine. At its lowest effective concentrations, taxol appears to block mitosis by kinetically stabilizing spindle microtubules and not by changing the mass of polymerized microtubules.